Tetrahydro-quinazolinone derivatives as TANK and PARP inhibitors

ABSTRACT

Compounds of the formula I 
                         
in which U, V and W have the meanings indicated in Claim  1 , are inhibitors of Tankyrase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to tetrahydro-quinazoline derivativeswhich inhibit the activity of Tankyrases (TANKs) andpoly(ADP-ribose)polymerase PARP-1. The compounds of this invention aretherefore useful in treating diseases such as cancer, multiplesclerosis, cardiovascular diseases, central nervous system injury anddifferent forms of inflammation. The present invention also providesmethods for preparing these compounds, pharmaceutical compositionscomprising these compounds, and methods of treating diseases utilizingpharmaceutical compositions comprising these compounds.

The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is a member ofthe PARP enzyme family. This growing family of enzymes consist of PARPssuch as, for example: PARP-1, PARP-2, PARP-3 and Vault-PARP; andTankyrases (TANKs), such as, for example: TANK-1 and TANK-2. PARP isalso referred to as poly(adenosine 5′-diphospho-ribose) polymerase orPARS (poly(ADP-ribose) synthetase).

TANK-1 seems to be required for the polymerization of mitoticspindle-associated poly(ADP-ribose). The poly(ADP-ribosyl)ation activityof TANK-1 might be crucial for the accurate formation and maintenance ofspindle bipolarity. Furthermore, PARP activity of TANK-1 has been shownto be required for normal telomere separation before anaphase.Interference with tankyrase PARP activity results in aberrant mitosis,which engenders a transient cell cycle arrest, probably due to spindlecheckpoint activation, followed by cell death. Inhibition of tankyrasesis therefore expected to have a cytotoxic effect on proliferating tumorcells (WO 2008/107478).

PARP inhibitors are described by M. Rouleau et al. in Nature Reviews,Volume 10, 293-301 in clinical cancer studies (Table 2, page 298).

According to a review by Horvath and Szabo (Drug News Perspect 20(3),April 2007, 171-181) most recent studies demonstrated that PARPinhibitors enhance the cancer cell death primarily because theyinterfere with DNA repair on various levels. More recent studies havealso demonstrated that PARP inhibitors inhibit angiogenesis, either byinhibiting growth factor expression, or by inhibiting growthfactor-induced cellular proliferative responses. These findings mightalso have implications on the mode of PARP inhibitors' anticancereffects in vivo.

Also a study by Tentori et al. (Eur. J. Cancer, 2007, 43 (14) 2124-2133)shows that PARP inhibitors abrogate VEGF or placental growthfactor-induced migration and prevent formation of tubule-like networksin cell-based systems, and impair angiogenesis in vivo. The study alsodemonstrates that growth factor-induced angiogenesis is deficient inPARP-1 knock-out mice. The results of the study provide evidence fortargeting PARP for anti-angiogenesis, adding novel therapeuticimplications to the use of PARP inhibitors in cancer treatment.

Defects in conserved signaling pathways are well known to play key rolesin the origins and behavior of essentially all cancers (E. A. Fearon,Cancer Cell, Vol. 16, Issue 5, 2009, 366-368). The Wnt pathway is atarget for anti-cancer therapy. A key feature of the Wnt pathway is theregulated proteolysis (degradation) of β-catenin by the β-catenindestruction complex. Proteins like WTX, APC or Axin are involved in thedegradation process. A proper degradation of β-catenin is important toavoid an inappropriate activation of the Wnt pathway which has beenobserved in many cancers. Tankyrases inhibit activity of Axin and henceinhibit the degradation of β-catenin. Consequently, tankyrase inhibitorsincrease degradation of β-catenin. A recent paper in the journal Naturenot only offers important new insights into proteins regulating Wntsignaling but also further supports the approach to antagonize β-cateninlevels and localization via small molecules (Huang et al., 2009; Nature,Vol 461, 614-620). The compound XAV939 inhibits growth of DLD-1-cancercells. They found that XAV9393 blocked Wnt-stimulated accumulation ofβ-catenin by increasing the levels of the AXIN1 and AXIN2 proteins.Subsequent work by the authors established that XAV939 regulates AXINlevels via inhibition of tankyrases 1 and 2 (TNKS1 and TNKS2), both ofwhich are members of the poly(ADP-ribose) polymerase (PARP) proteinfamily (S. J. Hsiao et al., Biochimie 90, 2008, 83-92).

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit Tankyrase 1 and 2, to compositions which comprise thesecompounds, and to processes for the use thereof for the treatment ofTANK-induced diseases and complaints.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of TANKs. In addition,they are particularly suitable for use in diagnostic methods fordiseases in connection with unregulated or disturbed TANK activity.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed are assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

PRIOR ART

Other tetrahydro-quinazoline derivatives with histamine H4 receptormodulating activity are described in WO 2011/078143.

Other tetrahydro-quinazoline derivatives with antitumor activity aredescribed in WO 2006/094604.

Syntheses of other tetrahydro-quinazoline derivatives are described bySekiya et al. in Chem. Pharm. Bull. 29(4), 948-954 (1981).

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   U denotes CH₂ or CHR²,-   V denotes CH₂, CHR² or CO,-   W denotes NR¹ or CR³R⁶,    -   or denotes NH, if U or V denote CHR²,-   R¹ denotes Ar, Het, COA, COAr¹, COHet, CO(CH₂)_(n)NR⁴R⁵,    (CH₂)_(n)Het, (CH₂)_(n)CONHAr, (CH₂)_(n)CONHHet, (CH₂)_(n)CONR⁴R⁵,    (CH₂)_(n)OH, (CH₂)_(n)OA or (CH₂)_(n)NR⁴R⁵,-   R² denotes A, Ar¹, Hal, CN, COA, COOH, COOA, CONR⁴R⁵, SO₂NR⁴R⁵,    (CH₂)_(n)OH or (CH₂)_(n)NR⁴R⁵,-   R³ denotes H, OH or OA,-   R⁴, R⁵ each, independently of one another, denote H or A,-   R⁶ denotes A or Ar¹,-   Ar denotes phenyl, which is mono-, di- or trisubstituted by Hal, A,    O(CH₂)_(p)Cyc, Alk, (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)COOH,    (CH₂)_(n)COOA, S(O)_(m)A, phenoxy, benzyloxy, (CH₂)_(n)NH₂,    (CH₂)_(n)NHA, (CH₂)_(n)NA₂, (CH₂)_(n)CN, NO₂, (CH₂)_(n)CONH₂,    (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, SO₂NH₂, SO₂NHA, SO₂NA₂, NHCONH₂,    (CH₂)_(n)NHCOA, (CH₂)_(n)NHCOAlk, NHCOCH═CH(CH₂)_(p)NA₂, CHO, COA,    SO₃H, O(CH₂)_(p)NH₂, O(CH₂)_(p)NHCOOA, O(CH₂)_(p)NHA, O(CH₂)_(p)NA₂,    NH(CH₂)_(p)NH₂, NH(CH₂)_(p)NHCOOA, NH(CH₂)_(p)NHA, NH(CH₂)_(p)NA₂,    NHCOHet³, COHet³, (CH₂)_(n)Het³, O(CH₂)_(n)Het³ and/or    O(CH₂)_(n)CH(OH)(CH₂),-   Ar¹ denotes phenyl, which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)COOH,    (CH₂)_(n)COOA, S(O)_(m)A, phenoxy, benzyloxy, (CH₂)_(n)NH₂,    (CH₂)_(n)NHA, (CH₂)_(n)NA₂, (CH₂)_(n)CN, NO₂, (CH₂)_(n)CONH₂,    (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, SO₂NH₂, SO₂NHA, SO₂NA₂, NHCONH₂,    (CH₂)_(n)NHCOA, CHO, COA and/or SO₃H,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di-, tri- or tetrasubstituted by Hal, A,    (CH₂)_(n)Het³, OHet³, NH(CH₂)_(n)Het³, (CH₂)_(n)COOH, (CH₂)_(n)COOA,    phenyl, benzyl, CHO, COA, (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂,    CN, (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(p)CH(OH)(CH₂)_(p)OH,    (CH₂)_(p)CH(OH)(CH₂)_(p)OA, NH(CH₂)_(p)NH₂, NHSO₂A, NASO₂A, SO₂A,    (CH₂)_(n)CONR⁴R⁵, (CH₂)_(n)SO₂NR⁴R⁵ and/or ═O,-   Het³ denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di-, tri- or tetrasubstituted by A, Hal,    (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂, (CH₂)_(n)OH, (CH₂)_(n)OA,    COOA, Ar³ and/or ═O,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    1-7H atoms may be replaced by F and/or Cl and/or in which one or two    non-adjacent CH₂ groups may be replaced by O, NH, S, SO, SO₂ and/or    by CH═CH groups, Cyc denotes cyclic alkyl having 3-7 C atoms,-   Alk denotes alkenyl or alkinyl having 2, 3, 4, 5 or 6 C-atoms,-   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or    trisubstituted by Hal and/or A,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1 or 2,-   n denotes 0, 1, 2, 3 or 4,-   p denotes 1, 2, 3 or 4,    and pharmaceutically usable solvates, salts, tautomers and    stereoisomers thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

The invention relates to compounds of formula I and their tautomers offormula Ia

Moreover, the invention relates to pharmaceutically acceptablederivatives of compounds of formula I.

The term solvates of the compounds is taken to mean adductions of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are, for example, mono- or dihydrates oralkoxides.

It is understood, that the invention also relates to the solvates of thesalts. The term pharmaceutically acceptable derivatives is taken tomean, for example, the salts of the compounds according to the inventionand also so-called prodrug compounds.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound of formula I that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a compound of formula I.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a compound of formula I that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable salts, solvates, tautomers andstereoisomers thereof, characterised in that

a compound of the formula II

is reacted with a compound of the formula III

in which U, V and W have the meanings indicated in claim 1,and/ora base or acid of the formula I is converted into one of its salts.

Above and below, the radicals U, V and W have the meanings indicated forthe formula I, unless expressly stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethyl-propyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoro-ethyl.

Moreover, A denotes preferably CH₂OCH₃, CH₂CH₂OH, CH₂NHCH₂ or NHCH₂CH₃.

Cyc denotes cyclic alkyl having 3-7 C atoms, preferably denotescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Alk denotes unbranched or branched alkenyl or alkinyl having 2, 3, 4, 5or 6 C-atoms, preferably denotes isopropenyl, prop-2-inyl, vinyl oderallyl.

U denotes preferably CH₂.

V denotes preferably CH₂.

W denotes preferably NR¹ or denotes NH, if U or V denote CHR².

W very particularly preferably denotes NR¹.

R² denotes preferably A, Ar¹, CONR⁴R⁵ or (CH₂)_(n)OH.

R⁴ denotes preferably H, Methyl, Ethyl, Propyl oder Butyl.

R⁵ denotes preferably H, Methyl, Ethyl, Propyl oder Butyl.

Ar denotes preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)-phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)-phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-formylphenyl, o-, m- orp-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-[2-(morpholin-4-yl)ethoxy]phenyl, o-, m- orp-[3-(N,N-diethyl-amino)propoxy]phenyl, furthermore preferably 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di-chloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar furthermore preferably denotes phenyl, which is mono-, di- ortrisubstituted by Hal, (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CN,(CH₂)_(n)CONH₂, (CH₂)_(n)CONHA and/or (CH₂)_(n)CONA₂.

Ar¹ denotes preferably phenyl.

Ar³ denotes preferably phenyl.

Irrespective of further substitutions, Het denotes preferably 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-indolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl,azabicyclo-[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Irrespective of further substitutions, Het can thus also denote,preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, dihydro-pyrazolyl, dihydro-pyridyl, dihydropyranyl, furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl,oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, quinolyl,isoquinolyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, indazolyl orbenzothiadiazolyl, each of which is unsubstituted or mono-, di- ortrisubstituted by (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CONR⁴R⁵,(CH₂)_(n)SO₂NR⁴R⁵ and/or ═O.

Irrespective of further substitutions, Het³ denotes preferably 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-indolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl,azabicyclo-[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Irrespective of further substitutions, Het can thus also denote,preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het³ preferably denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, 2,3-dihydro-pyrazolyl, 1,2-dihydro-pyridyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrimidinyl, triazolyl,4,5-dihydro-1H-[1,2,4]triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,tetrahydro-benzothiophenyl, pyridazinyl or pyrazinyl, each of which isunsubstituted or mono-, di-, tri- or tetrasubstituted by A, (CH₂)_(n)OH,(CH₂)_(n)OA and/or ═O.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ig, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia Ar denotes phenyl, which is mono-, di- or trisubstituted by    Hal, (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CN, (CH₂)_(n)CONH₂,    (CH₂)_(n)CONHA and/or (CH₂)_(n)CONA₂;-   in Ib Ar¹ denotes phenyl;-   in Ic Het denotes piperidinyl, piperazinyl, pyrrolidinyl,    morpholinyl, dihydro-pyrazolyl, dihydro-pyridyl, dihydropyranyl,    furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,    isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,    triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl,    pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl,    indolyl, benzo-1,3-dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,    indazolyl or benzothiadiazolyl, each of which is unsubstituted or    mono-, di- or trisubstituted by (CH₂)_(n)OH, (CH₂)_(n)OA,    (CH₂)_(n)CONR⁴R⁵, (CH₂)_(n)SO₂NR⁴R⁵ and/or ═O;-   in Id Het³ denotes piperidinyl, piperazinyl, pyrrolidinyl,    morpholinyl, 2,3-dihydro-pyrazolyl, 1,2-dihydro-pyridyl, furyl,    thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,    thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,    4,5-dihydro-1H-[1,2,4]triazolyl, tetrazolyl, oxadiazolyl,    thiadiazolyl, tetrahydro-benzothiophenyl, pyridazinyl or pyrazinyl,    each of which is unsubstituted or mono-, di-, tri- or    tetrasubstituted by A, (CH₂)_(n)OH, (CH₂)_(n)OA and/or ═O;-   in Ie A denotes unbranched or branched alkyl having 1-10 C atoms, in    which 1-7H atoms may be replaced by F and/or Cl;-   in If U denotes CH₂,    -   V denotes CH₂, CHR² or CO,    -   W denotes NR¹ or CR³R⁶,        -   or denotes NH, if U or V denote CHR²,    -   R¹ denotes Ar, Het, COA, COAr¹, COHet, CO(CH₂)_(n)NR⁴R⁵,        (CH₂)_(n)Het, (CH₂)_(n)CONHAr, (CH₂)_(n)CONHHet,        (CH₂)_(n)CONR⁴R⁵, (CH₂)_(n)OH, (CH₂)_(n)OA or (CH₂)_(n)NR⁴R⁵,    -   R² denotes A, Ar¹, CONR⁴R⁵ or (CH₂)_(n)OH,    -   R³ denotes H, OH or OA,    -   R⁴, R⁵ each, independently of one another, denote H or A,    -   R⁶ denotes A or Ar¹,    -   Ar denotes phenyl, which is mono-, di- or trisubstituted by al,        (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CN, (CH₂)_(n)CONH₂,        (CH₂)_(n)CONHA and/or (CH₂)_(n)CONA₂,    -   Ar¹ denotes phenyl,    -   Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,        dihydro-pyrazolyl, dihydro-pyridyl, dihydropyranyl, furyl,        thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,        thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,        tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl,        quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, indazolyl or        benzothiadiazolyl, each of which is unsubstituted or mono-, di-        or trisubstituted by (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CONR⁴R⁵,        (CH₂)_(n)SO₂NR⁴R⁵ and/or ═O,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F and/or Cl,    -   n denotes 0, 1, 2, 3 or 4;-   in Ig U denotes CH₂,    -   V denotes CH₂,    -   W denotes NR¹,    -   R¹ denotes Ar, Het, COA, COAr¹, COHet, CO(CH₂)_(n)NR⁴R⁵,        (CH₂)_(n)Het, (CH₂)_(n)CONHAr, (CH₂)_(n)CONHHet,        (CH₂)_(n)CONR⁴R⁵, (CH₂)_(n)OH, (CH₂)_(n)OA or (CH₂)_(n)NR⁴R⁵,    -   R⁴, R⁵ each, independently of one another, denote H or A,    -   Ar denotes phenyl, which is mono-, di- or trisubstituted by Hal,        (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CN, (CH₂)_(n)CONH₂,        (CH₂)_(n)CONHA and/or (CH₂)_(n)CONA₂,    -   Ar¹ denotes phenyl,    -   Het denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,        dihydro-pyrazolyl, dihydro-pyridyl, dihydropyranyl, furyl,        thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,        thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,        tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl,        quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, indazolyl or        benzothiadiazolyl, each of which is unsubstituted or mono-, di-        or trisubstituted by (CH₂)_(n)OH, (CH₂)_(n)OA, (CH₂)_(n)CONR⁴R⁵,        (CH₂)_(n)SO₂NR⁴R⁵ and/or ═O,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F and/or Cl,    -   n denotes 0, 1, 2, 3 or 4,        and pharmaceutically usable salts, solvates, tautomers and        stereoisomers thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds of the formulae II and III are generally known.If they are novel, however, they can be prepared by methods known perse.

Compounds of the formula I can preferably be obtained by reacting in afirst step the compound of the formula II with a compound of the formulaIII.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −10° and180°, normally between 30° and 170°, in particular between about 60° andabout 160°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to isoamylalcohol.

Free amino groups can furthermore be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogen-phosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethyl-piperidine, glucamine, glucosamine,histidine, hydrabamine, isopropyl-amine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, aprodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labelled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labelled compound of theformula I into which, for example, a radioisotope, such as ³H or ¹⁴C,has been incorporated is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodiment of thepresent invention. An isotope-labelled compound of the formula I canusually be prepared by carrying out the procedures disclosed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts, solvates and physiologicallyfunctional derivatives thereof can also be administered in the form ofliposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention is generally in the range from 0.1 to 100 mg/kg of body weightof the recipient (mammal) per day and particularly typically in therange from 1 to 10 mg/kg of body weight per day. Thus, the actual amountper day for an adult mammal weighing 70 kg is usually between 70 and 700mg, where this amount can be administered as a single dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptable salts,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically acceptable salts, solvates and stereoisomers    thereof, including mixtures thereof in all ratios,    -   and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically acceptable salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a subject at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with a compound of formula (I)can mean an amount capable of alleviating, in whole or in part, symptomsassociated with a disorder or disease, or slowing or halting furtherprogression or worsening of those symptoms, or preventing or providingprophylaxis for the disease or disorder in a subject having or at riskfor developing a disease disclosed herein, such as inflammatoryconditions, immunological conditions, cancer or metabolic conditions.

In one embodiment an effective amount of a compound of formula (I) is anamount that inhibits a tankyrase in a cell, such as, for example, invitro or in vivo. In some embodiments, the effective amount of thecompound of formula (I) inhibits tankyrase in a cell by 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity oftankyrase in an untreated cell. The effective amount of the compound offormula (I), for example in a pharmaceutical composition, may be at alevel that will exercise the desired effect; for example, about 0.005mg/kg of a subject's body weight to about 10 mg/kg of a subject's bodyweight in unit dosage for both oral and parenteral administration.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of cancer, multiplesclerosis, cardiovascular diseases, central nervous system injury anddifferent forms of inflammation.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts and solvates thereoffor the preparation of a medicament for the treatment or prevention ofcancer, multiple sclerosis, cardiovascular diseases, central nervoussystem injury and different forms of inflammation.

Examples of inflammatory diseases include rheumatoid arthritis,psoriasis, contact dermatitis, delayed hypersensitivity reaction and thelike.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment or prevention of atankyrase-induced disease or a tankyrase-induced condition in a mammal,in which to this method a therapeutically effective amount of a compoundaccording to the invention is administered to a sick mammal in need ofsuch treatment. The therapeutic amount varies according to the specificdisease and can be determined by the person skilled in the art withoutundue effort.

The expression “tankyrase-induced diseases or conditions” refers topathological conditions that depend on the activity of one or moretankyrases. Diseases associated with tankyrase activity include cancer,multiple sclerosis, cardiovascular diseases, central nervous systeminjury and different forms of inflammation.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, for theuse for the treatment of diseases in which the inhibition, regulationand/or modulation inhibition of tankyrase plays a role.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, for theuse for the inhibition of tankyrase.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, for theuse for the treatment of cancer, multiple sclerosis, cardiovasculardiseases, central nervous system injury and different forms ofinflammation.

The present invention specifically relates to methods for treating orpreventing cancer, multiple sclerosis, cardiovascular diseases, centralnervous system injury and different forms of inflammation, comprisingadministering to a subject in need thereof an effective amount of acompound of formula I or a pharmaceutically acceptable salt, tautomer,stereoisomer or solvate thereof.

In another aspect provided herein are methods of inhibiting tankyrase ina cell expressing said kinase, comprising contacting said cell with aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt, tautomer, stereoisomer or solvate thereof.

Representative inflammatory conditions that compounds of formula I areuseful for treating or preventing include, but are not limited to,non-ANCA (anti-neutrophil cytoplasmic autoantibody) vasculitis (e.g.,wherein Syk function is associated with neutrophil adhesion, diapedesisand/or activation), psoriasis, asthma, allergic rhinitis, allergicconjunctivitis, chronic urticaria, hives, anaphylaxis, bronchitis,chronic obstructive pulmonary disease, cystic fibrosis, inflammatorybowel disease, irritable bowel syndrome, gout, Crohn's disease, mucouscolitis, ulcerative colitis, allergy to intestinal antigens (such asgluten enteropathy), diabetes (e.g., Type I diabetes and Type IIdiabetes) and obesity. In some embodiments, the inflammatory conditionis a dermatologic condition, such as, for example, psoriasis, urticaria,hives, eczema, scleroderma, or dermatitis. In other embodiments, theinflammatory condition is an inflammatory pulmonary condition, such as,for example, asthma, bronchitis, chronic obstructive pulmonary disease(COPD), or adult/acute respiratory distress syndrome (ARDS). In otherembodiments, the inflammatory condition is a gastrointestinal condition,such as, for example, inflammatory bowel disease, ulcerative colitis,Crohn's disease, idiopathic inflammatory bowel disease, irritable bowelsyndrome, or spastic colon.

Representative cancers that compounds of formula I are useful fortreating or preventing include, but are not limited to, cancer of thehead, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas,brain, central nervous system, solid tumors and blood-borne tumors.

Representative cardiovascular diseases that compounds of formula I areuseful for treating or preventing include, but are not limited to,restenosis, atherosclerosis and its consequences such as stroke,myocardial infarction, ischemic damage to the heart, lung, gut, kidney,liver, pancreas, spleen or brain.

The present invention relates to a method of treating a proliferative,autoimmune, anti inflammatory or infectious disease disorder thatcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula I.

Preferably, the present invention relates to a method wherein thedisease is a cancer.

Particularly preferable, the present invention relates to a methodwherein the disease is a cancer, wherein administration is simultaneous,sequential or in alternation with administration of at least one otheractive drug agent.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic/DNA-damaging agents andcombinations thereof, as used in medical oncology, such as alkylatingagents (for example cis-platin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chloroambucil, busulphan and nitrosoureas);anti-metabolites (for example antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (forexample anthracyclines, like adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vinca alkaloids, likevincristine, vinblastine, vindesine and vinorelbine, and taxoids, liketaxol and taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins, like etoposide and teniposide, amsacrine,topotecan, irinotecan and camptothecin) and cell-differentiating agents(for example all-trans-retinoic acid, 13-cis-retinoic acid andfenretinide);

(ii) cytostatic agents, such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordownregulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progesterones (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase, such as finasteride;

(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors, like marimastat, and inhibitors ofurokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors, such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;

(v) antiangiogenic agents, such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in published international patentapplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin);

(vi) vessel-damaging agents, such as combretastatin A4 and compoundsdisclosed in international patent applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-Ras antisense;

(viii) gene therapy approaches, including, for example, approaches forreplacement of aberrant genes, such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme, and approaches for increasing patient toleranceto chemotherapy or radiotherapy, such as multi-drug resistance genetherapy; and

(ix) immunotherapy approaches, including, for example, ex-vivo andin-vivo approaches for increasing the immunogenicity of patient tumourcells, such as transfection with cytokines, such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches for decreasing T-cell anergy, approaches using transfectedimmune cells, such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines, and approaches usinganti-idiotypic antibodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfaneProcarbazine Ifosfamide Altretamine Melphalane Estramustin phosphateHexamethylmelamine Mechlorethamine Thiotepa Streptozocin chlorambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 (Hoffrnann-La Iproplatin Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycine 5-fluoruracilFludarabine Floxuridine Pentostatin 2-chlordesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluordesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicine Exatecan mesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet(TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350(BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour antibioticsDactinomycin (Actinomycin Amonafide D) Azonafide Doxorubicin(Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole ValrubicinLosoxantrone Daunorubicin (Daunomycin) Bleomycin sulfate (Blenoxan)Epirubicin Bleomycin acid Therarubicin Bleomycin A Idarubicin BleomycinB Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) PorfiromycinGPX-100 (Gem Cyanomorpholinodoxorubicin Pharmaceuticals) Mitoxantron(Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel(GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (CellTherapeutics) Vincristine IDN 5109 (Bayer) Vinorelbine A 105972 (Abbott)Vindesine A 204197 (Abbott) Dolastatine 10 (NCI) LU 223651 (BASF)Rhizoxine (Fujisawa) D 24851 (ASTA Medica) Mivobulin (Warner-Lambert)ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A(Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) EpothiloneB (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel(Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly)!DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE(Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS)BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE)Aromatase inhibitors Aminoglutethimide Exemestan Letrozole Atamestan(BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestanThymidylatesynthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (Paligent)Thymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl Arglabin(NuOncology Labs) Tipifarnib (Johnson & transferase Ionafarnib(Schering- Johnson) inhibitors Plough) Perillyl alcohol (DOR BAY-43-9006(Bayer) BioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase SAHA (Aton Pharma) (Titan)inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) inhibitors/Laboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (BritishBiotech) Tezacitabine (Aventis) reductase Gallium maltolate (Titan)Didox (Molecules for Health) inhibitors Triapine (Vion) TNF-alphaagonists/ Virulizin (Lorus Revimide (Celgene) antagonists Therapeutics)CDC-394 (Celgene) Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi)receptor antagonists ZD-4054 (AstraZeneca) Retinoic acid Fenretinide(Johnson & Alitretinoin (Ligand) receptor agonists Johnson) LGD-1550(Ligand) Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarzinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccine (CTL !3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVax) Hormonal and anti-Oestrogens Prednisone hormonal agents Conjugated oestrogensMethylprednisolone Ethinylestradiol Prednisolone chlorotrianiseneAminoglutethimide Idenestrol Leuprolide Hydroxyprogesteron caproateGoserelin Medroxyprogesterone Leuporelin Testosterone Testosteronpropionate Bicalutamide Fluoxymesterone Flutamide MethyltestosteroneOctreotide Diethylstilbestrol Nilutamide Megestrol Mitotan TamoxifenP-04 (Novogen) Toremofin 2-Methoxyoestradiol Dexamethasone (EntreMed)Arzoxifen (Eli Lilly) Photodynamic agents Talaporfin (Light Sciences)Pd-Bacteriopheophorbid Theralux (Theratechnologies) (Yeda)Motexafin-Gadolinium Lutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics)Hypericin Tyrosin kinase Imatinib (Novartis) Kahalid F (PharmaMar)inhibitors Leflunomide CEP- 701 (Cephalon) (Sugen/Pharmacia) CEP-751(Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (OncogeneScience) PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine(Genaera) Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone)SU6668 (Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210(Medarex) ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis)MDX-447 (Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016(GlaxoSmithKline) IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth)Various agents SR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor,Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic-AMP Ranpirnase(ribonuclease agonist, Ribapharm) stimulant, Alfacell) Alvocidib (CDKinhibitor, Galarubicin (RNA synthesis Aventis) inhibitor, Dong-A) CV-247(COX-2 Inhibitor, Ivy Tirapazamine (reducing agent, Medical) SRIInternational) P54 (COX-2 inhibitor, N-Acetylcysteine (reducingPhytopharm) agent, Zambon) CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaBstimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3 antagonist,3CPA (NF-kappaB inhibitor, GlycoGenesys) Active Biotech) G17DT immunogen(gastrin Seocalcitol (vitamin-D inhibitor, Aphton) receptor agonist,Leo) Efaproxiral (Oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, TransMolecular) PI-88 (heparanase inhibitor, Eflornithin(ODC inhibitor, Progen) ILEX Oncology) Tesmilifen (histamine Minodronicacid (osteoclasts antagonist, YM BioSciences) inhibitor, Yamanouchi)Histamine (Histamine-H2 Indisulam (p53 stimulant, receptor agonist,Maxim) Eisai) Tiazofurin (IMPDH inhibitor, Aplidin (PPT inhibitor,Ribapharm) PharmaMar) Cilengitide (integrin Rituximab (CD20 antibody,antagonist, Merck KGaA) Genentech) SR-31747 (IL-1 antagonist, Gemtuzumab(CD33 Sanofi-Synthelabo) antibody, Wyeth Ayerst) CCI-779 (mTOR kinasePG2 (haematopoiesis inhibitor, Wyeth) promoter, Pharmagenesis) Exisulind(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)CP-461 (PDE-V inhibitor, Cell Triacetyluridine (uridine Pathways)prodrug, Wellstat) AG-2037 (GART inhibitor, SN-4071 (sarcoma agent,Pfizer) Signature BioScience) WX-UK1 (plasminogen TransMID-107 ™activator inhibitor, Wilex) (immunotoxin, KS PBI-1402 (PMN stimulant,Biomedix) ProMetic LifeSciences) PCK-3145 (apoptosis Bortezomib(proteasome promoter, Procyon) inhibitor, Millennium) Doranidazole(apoptosis SRL-172 (T-cell stimulant, promoter, Pola) SR Pharma) CHS-828(cytotoxic agent, TLK-286 (glutathione-S- Leo) transferase inhibitor,Telik) Trans-retinic acid PT-100 (growth factor (differentiator, NIH)agonist, Point Therapeutics) MX6 (apoptosis promoter, Midostaurin (PKCinhibitor, MAXIA) Novartis) Apomine (apoptosis promoter, Bryostatin-1(PKC stimulant, ILEX Oncology) GPC Biotech) Urocidin (apoptosis CDA-II(apoptosis promoter, promoter, Bioniche) Everlife) Ro-31-7453 (apoptosisSDX-101 (apoptosis promoter, La Roche) promoter, Salmedix) Brostallicin(apoptosis Ceflatonin (apoptosis promoter, Pharmacia) promoter,ChemGenex)

The disclosed compounds of the formula I and pharmaceutically acceptablesolvates, salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios, preferably can be administered in combinationwith immunomodulators, preferably with anti-PDL-1- or IL-12.

The following abbreviations refer respectively to the definitions below:aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz(Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM(millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), L(microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF(dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d₆ (deuterateddimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethylammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MeOH (methanol), MgSO₄ (magnesium sulfate), MS (massspectrometry), MTBE (Methyl tert-butyl ether), NaHCO₃ (sodiumbicarbonate), NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR(Nuclear Magnetic Resonance), PyBOP(benzotriazole-1-yl-oxy-trispyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SPE(solid phase extraction), TBTU(2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).

Description of the In Vitro Assays

Abbreviations:

GST=Glutathione-5-transferase

FRET=Fluorescence resonance energy transfer

HTRF®=(homogenous time resolved fluorescence)

HEPES=4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid buffer

DTT=Dithiothreitol

BSA=bovine serum albumin

CHAPS=detergent;

CHAPS=3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate

Streptavidin-XLent® is a high grade streptavidin-XL665 conjugate forwhich the coupling conditions have been optimized to yield a conjugatewith enhanced performances for some assays, particularly those requiringhigh sensitivity.

Biochemical Activity Testing of Tankyrase 1 and 2: Autoparsylation Assay

The autoparsylation assay was run in two steps: the enzymatic reactionin which GST-tagged Tankyrase-1, resp Tankyrase-2 transferredbiotinylated ADP-ribose to itself from biotinylated NAD as co-substrateand the detection reaction where a time resolved FRET between cryptatelabelled anti-GST bound to the GST tag of the enzyme and Xlent®labelled-streptavidin bound the biotin-parsylation residue was analysed.The autoparsylation activity was detectable directly via the increase inHTRF signal.

The autoparsylation assay was performed as 384-well HTRF® (Cisbio,Codolet, France) assay format in Greiner low volume nb 384-wellmicrotiter plates and was used for high throughput screen. 250 nMGST-tagged Tankyrase-1 (1023-1327 aa), respectively about 250 nMGST-tagged Tankyrase-2 (873-1166 aa) and 5 μM bio-NAD (Biolog, Lifescience Inst., Bremen, Germany) as co-substrate were incubated in atotal volume of 5 μl (50 mM HEPES, 4 mM Mg-chloride, 0.05% PluronicF-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) in the absence or presence of thetest compound (10 dilution concentrations) for 90 min at 30° C. Thereaction was stopped by the addition of 1 μl 50 mM EDTA solution. 2 μlof the detection solution (1.6 μM SA-Xlent® (Cisbio, Codolet, France),7.4 nM Anti-GST-K® (Eu-labelled anti-GST, Cisbio, Codolet, France) in 50mM HEPES, 800 mM KF, 0.1% BSA, 20 mM EDTA, 0.1% CHAPS, pH 7.0) wereadded. After 1 h incubation at room temperature the HTRF was measuredwith an Envision multimode reader (Perkin Elmer LAS Germany GmbH) atexcitation wavelength 340 nm (laser mode) and emission wavelengths 615nm and 665 nm. The ratio of the emission signals was determined. Thefull value used was the inhibitor-free reaction. The pharmacologicalzero value used was XAV-939 (Tocris) in a final concentration of 5 μM.The inhibitory values (IC50) were determined using either the programSymyx Assay Explorer® or Condosseo® from GeneData.

Measurement of Cellular Inhibition of Tankyrase

Since Tankyrases have been described to modulate cellular level of Axin2(Huang et al., 2009; Nature) the increase of Axin2 level is used asread-out for determination of cellular inhibition of Tankyrases in aLuminex based assay.

Cells of the colon carcinoma cell line DLD1 are plated in 96 well plateswith 1.5×10⁴ cells per well. Next day, cells are treated with aserial-dilution of test compound in seven steps as triplicates with afinal DMSO concentration of 0.3%. After 24 hours, cells are lysed inlysis buffer (20 mM Tris/HCl pH 8.0, 150 mM NaCl, 1% NP40, 10% Glycerol)and lysates are cleared by centrifugation through a 96 well filter plate(0.65 μm). Axin2 protein is isolated from cell lysates by incubationwith a monoclonal anti-Axin2 antibody (R&D Systems #MAB6078) that isbound to fluorescent carboxybeads. Then, bound Axin2 is specificallydetected with a polyclonal anti-Axin2 antibody (Cell Signaling #2151)and an appropriate PE-fluorescent secondary antibody. The amount ofisolated Axin2 protein is determined in a Luminex²⁰⁰ machine (LuminexCorporation) according to the manufacturer's instruction by counting 100events per well. Inhibition of Tankyrase by test compounds results inhigher levels of Axin2 which directly correlates with an increase ofdetectable fluorescence. As controls cells are treated with solventalone (neutral control) and with a Tankyrase reference inhibitor IWR-2(3E-06 M) which refers as control for maximum increase of Axin2. Foranalysis, the obtained data were normalized against the untreatedsolvent control and fitted for determination of the EC₅₀ values usingthe Assay Explorer software (Accelrys).

Biochemical Activity Testing of PARP-1: Autoparsylation Assay

The autoparsylation assay was run in two steps: the enzymatic reactionin which His-tagged Parp-1 transferred biotinylatedADP-ribose/ADP-ribose to itself from biotinylated NAD/NAD asco-substrate and the detection reaction where a time resolved FRETbetween cryptate labelled anti-His antibody bound to the His tag of theenzyme and Xlent® labelled-streptavidin bound the biotin-parsylationresidue was analysed. The autoparsylation activity was detectabledirectly via the increase in HTRF signal.

The autoparsylation assay was performed as 384-well HTRF® (Cisbio,Codolet, France) assay format in Greiner low volume nb 384-wellmicrotiter plates. 35 nM His-tagged Parp-1 (human, recombinant, EnzoLife Sciences GmbH, Lörrach, Germany) and a mixture of 125 nM bio-NAD(Biolog, Life science Inst., Bremen, Germany) and 800 nM NAD asco-substrate were incubated in a total volume of 6 μl (100 mM Tris/HCl,4 mM Mg-chloride, 0.01% IGEPAL® CA630, 1 mM DTT, 0.5% DMSO, pH 8, 13ng/μl activated DNA (BPS Bioscience, San Diego, US)) in the absence orpresence of the test compound (10 dilution concentrations) for 150 minat 23° C. The reaction was stopped by the addition of 4 μl of theStop/detection solution (70 nM SA-Xlent® (Cisbio, Codolet, France), 2.5nM Anti-His-K® (Eu-labelled anti-His, Cisbio, Codolet, France) in 50 mMHEPES, 400 mM KF, 0.1% BSA, 20 mM EDTA, pH 7.0). After 1 h incubation atroom temperature the HTRF was measured with an Envision multimode reader(Perkin Elmer LAS Germany GmbH) at excitation wavelength 340 nm (lasermode) and emission wavelengths 615 nm and 665 nm. The ratio of theemission signals was determined. The full value used was theinhibitor-free reaction. The pharmacological zero value used wasOlaparib (LClabs, Woburn, US) in a final concentration of 1 μM. Theinhibitory values (IC50) were determined using either the program SymyxAssay Explorer® or Condosseo® from GeneData.

Biochemical Activity Testing of TNKS 1 and 2: Activity ELISA(Autoparsylation Assay)

For analysis of autoparsylation activity of TNKS 1 and 2 an activityELISA was performed: In the first step GST tagged TNKS was captured on aGlutathione coated plate. Then the activity assay with biotinylated NADwas performed in the absence/presence of the compounds. During theenzymatic reaction GST tagged TNKS transferred biotinylated ADP-riboseto itself from biotinylated NAD as co-substrate. For the detectionstreptavidin-HRP conjugate was added that bound to the biotinylated TNKSand was thereby captured to the plates. The amount of biotinylated respautoparsylated TNKS was detected with a luminescence substrate for HRP.The level of the luminescence signal correlated directly with the amountof autoparsylated TNKS and therefore with activity of TNKS.

The activity ELISA was performed in 384 well Glutathione coatedmicrotiter plates (Express capture Glutathione coated plate, Biocat,Heidelberg, Germany). The plates were pre-equilibrated with PBS. Thenthe plates were incubated with 50 μl 20 ng/well GST-tagged Tnks-1(1023-1327 aa, prepared in-house), respectively GST-tagged Tnks-2(873-1166 aa, prepared in-house) in assay buffer (50 mM HEPES, 4 mMMg-chloride, 0.05% Pluronic F-68, 2 mM DTT, pH 7.7) overnight at 4° C.The plates were washed 3 times with PBS-Tween-20. The wells were blockedby incubation at room temperature for 20 minutes with 50 μl blockingbuffer (PBS, 0.05% Tween-20, 0.5% BSA). Afterwards the plates werewashed 3 times with PBS-Tween-20. The enzymatic reaction was performedin 50 μl reaction solution (50 mM HEPES, 4 mM Mg-chloride, 0.05%Pluronic F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) with 10 μM bio-NAD(Biolog, Life science Inst., Bremen, Germany) as co-substrate in theabsence or presence of the test compound (10 dilution concentrations)for 1 hour at 30° C. The reaction was stopped by 3 times washing withPBS-Tween-20. For the detection 50 μl of 20 ng/μl Streptavidin, HRPconjugate (MoBiTec, Göttingen, Germany) in PBS/0.05% Tween-20/0.01% BSAwere added and the plates were incubated for 30 minutes at roomtemperature. After three times washing with PBS-Tween-20 50 μl ofSuperSignal ELISA Femto Maximum sensitivity substrate solution(ThermoFisherScientific (Pierce), Bonn, Germany) were added. Following a1 minute incubation at room temperature luminescence signals weremeasured with an Envision multimode reader (Perkin Elmer LAS GermanyGmbH) at 700 nm. The full value used was the inhibitor-free reaction.The pharmacological zero value used was XAV-939 (Tocris) in a finalconcentration of 5 μM. The inhibitory values (IC50) were determinedusing either the program Symyx Assay Explorer® or Condosseo® fromGeneData.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

m.p.=melting point

HPLC data provided in the examples described below (retention timegiven) were obtained as followed:

P: HPLC method:

gradient: 5.5 min; flow: 2.75 ml/min from 99:1 to 0:100 H₂O/acetonitrilwater+TFA (0.01% vol.); acetonitril+TFA (0.01% vol.)

column: Chromolith SpeedROD

RP 18e 50-4.6

wavelength: 220 nm

Merck Hitachi La Chrome instrument

N: HPLC-method:

gradient: 5.5 min; flow: 2.75 ml/min from 90:10 to 0:100 H₂O/ACNwater+TFA(0.01% Vol.); acetonitril+TFA (0.01% Vol.)

column: Chromolith SpeedROD RP 18e 50-4.6

wavelength: 220 nm

Merck Hitachi La Chrome instrument

¹H NMR was recorded on Bruker DPX-300, DRX-400 or AVII-400 spectrometer,using residual signal of deuterated solvent as internal reference.Chemical shifts (δ) are reported in ppm relative to the residual solventsignal (δ=2.49 ppm for ¹H NMR in DMSO-d₆). ¹H NMR data are reported asfollows: chemical shift (multiplicity, coupling constants, and number ofhydrogens). Multiplicity is abbreviated as follows: s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), br (broad).

The microwave chemistry is performed on a single mode microwave reactorEmrys™ Optimiser from Personal Chemistry.

Example 1.1.1 2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ylamine

A mixture of N-cyano-5-methylisothiourea (10 g; 86.84 mmol),cyclohexanone (90.7 ml; 868.37 mmol) and pyrrolidine (0.36 ml; 4.34mmol) is stirred at 150° C. for 30 min, and the pale-yellow reactionmixture is stirred at 150° C. for a further 60 h. The reaction mixtureis evaporated to dryness. The residue is dissolved in MeOH and purifiedby chromatography on an RP18ec silica-gel column of a CombiflashCompanion; yield: 5.09 g (27%), oil (purity: 88%).

Example 1.1 2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one

2-Methylsulfanyl-5,6,7,8-tetrahydroquinazolin-4-ylamine (5.09 g; 23.145mmol), 3-methyl-1-nitrosooxybutane (11.6 ml; 86.79 mmol) andtrifluoroacetic acid (23.2 ml; 300.89 mmol) are dissolved in chloroform(300 ml), the pale-yellow solution is warmed to 60° C. and stirred for 2h. The reaction mixture is diluted with dichloromethane and extractedwith 10% K₂CO₃. The aqueous phase is separated off and back-extractedonce with dichloromethane, NaCl is subsequently added, and the mixtureis extracted again with ethyl acetate. The combined organic phases aredried over Na₂SO₄, filtered and evaporated. The crude product obtainedin this way is adsorbed onto sorbent and purified by chromatography on aSI50 silica-gel column of a Combiflash Companion XL. After evaporationof the product fractions, the crystalline residue is triturated withdiethyl ether, filtered off by suction and dried in vacuo; yield: 2.0 g(57%), crystals.

Example 12-[4-(4-Fluorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A6”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-(4-fluorophenyl)piperazine (91.8 μl; 0.51 mmol) aresuspended in isoamyl alcohol (1 ml), and the mixture is irradiated inthe microwave (CEM Discover) at 150° C. for 2 h with stirring. Theprecipitated crystals are filtered off with suction, rinsed thoroughlywith ethanol and diethyl ether and filtered off with suction. The crudeproduct obtained in this way is rinsed again with hot ethanol anddiethyl ether, filtered off with suction and dried in vacuo at 50° C.;yield: 86 mg (50%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.09 (bs, 1H), 7.13-6.92 (m, 4H),3.73-3.61 (m, 4H), 3.15-3.03 (m, 4H), 2.42-2.35 (m, 2H), 2.29-2.20 (m,2H), 1.73-1.54 (m, 4H).

Example 22-[4-(3-Fluorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A5”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-(3-fluorophenyl)piperazine (82.6 μl; 0.51 mmol) are reactedin isoamyl alcohol (1 ml) in accordance with the procedure for Example 1and worked up; yield: 54 mg (32%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.0 (bs, 1H), 7.28-7.16 (m, 1H),6.84-6.72 (m, 2H), 6.60-6.50 (m, 1H), 3.70-3.62 (m, 4H), 3.26-3.18 (m,4H), 2.43-2.35 (m, 2H), 2.28-2.19 (m, 2H), 1.73-1.56 (m, 4H).

Example 32-[4-(3-Methoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A7”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol), 1-(3-methoxyphenyl)piperazine hydrochloride (116.5 mg; 0.51 mmol)and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol(1 ml) in accordance with the procedure for Example 1 (reaction time 4h) and worked up; yield: 79 mg (45%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.13 (bs, 1H), 7.17-7.05 (m, 1H),6.58-6.52 (m, 1H), 6.48 (t, J=2.3 Hz, 1H), 6.42-6.36 (m, 1H), 3.76-3.69(s, 3H), 3.71-3.61 (m, 4H), 3.21-3.09 (m, 4H), 2.43-2.33 (m, 2H),2.31-2.18 (m, 2H), 1.73-1.54 (m, 4H).

Example 42-[4-(4-Chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A8”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-(4-chlorophenyl)piperazine (100.2 mg; 0.51 mmol) are reactedin isoamyl alcohol (1 ml) in accordance with the procedure for Example 1and worked up; yield: 83 mg (47%), crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.14 (bs, 1H), 7.29-7.19 (m, 2H),7.04-6.91 (m, 2H), 3.75-3.58 (m, 4H), 3.23-3.11 (m, 4H), 2.43-2.32 (m,2H), 2.31-2.18 (m, 2H), 1.72-1.56 (m, 4H).

Example 52-[4-(2-Chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A9”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-(2-chlorophenyl)piperazine (84.9 μl; 0.51 mmol) are reactedin isoamyl alcohol (1 ml) in accordance with the procedure for Example 1and worked up; yield: 65 mg (37%), crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.12 (bs, 1H), 7.42 (dd, J=7.9, 1.6Hz, 1H), 7.35-7.26 (m, 1H), 7.23-7.13 (m, 1H), 7.11-7.01 (m, 1H),3.78-3.63 (m, 4H), 3.06-2.95 (m, 4H), 2.43-2.33 (m, 2H), 2.32-2.20 (m,2H), 1.74-1.57 (m, 4H).

Example 62-[4-(3-Chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A11”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol), 1-(3-chlorophenyl)piperazine hydrochloride (118.8 mg; 0.51 mmol)and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol(1 ml) in accordance with the procedure for Example 1 (reaction time 4h) and worked up; yield: 51 mg (29%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.13 (bs, 1H), 7.29-7.14 (m, 1H),7.04-6.87 (m, 2H), 6.86-6.74 (m, 1H), 3.77-3.56 (m, 4H), 3.26-3.13 (m,3H), 2.43-2.32 (m, 2H), 2.30-2.17 (m, 2H), 1.76-1.49 (m, 4H).

Example 72-[4-(2-Methoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A12”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-(2-methoxyphenyl)piperazine (98 mg; 0.51 mmol) are reactedin isoamyl alcohol (1 ml) in accordance with the procedure for Example 1(reaction time 4 h) and worked up; yield: 52 mg (30%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.07 (bs, 1H), 7.03-6.83 (m, 4H),3.79 (s, 3H), 3.70-3.61 (m, 4H), 3.01-2.92 (m, 4H), 2.42-2.33 (m, 2H),2.30-2.20 (m, 2H), 1.73-1.56 (m, 4H).

Example 82-(4-tert-Butylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A13”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-tert-butylpiperazine (72.5 mg; 0.51 mmol) are reacted inisoamyl alcohol (1 ml) in accordance with the procedure for Example 1and worked up; yield: 42 mg (28%), crystals.

Example 92-[4-(Piperidine-1-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A15”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and piperazin-1-ylpiperidin-1-ylmethanone (100.5 mg; 0.51 mmol)are reacted in isoamyl alcohol (1 ml) in accordance with the procedurefor Example 1. After a reaction time of 4 h,piperazin-1-ylpiperidin-1-ylmethanone (50.3 mg; 0.26 mmol) and isoamylalcohol (0.5 ml) are again added, and the mixture is again irradiated inthe microwave for 4 h. The crystals obtained after conventional work-upare dissolved in acetonitrile and water and freeze-dried; yield: 17 mg(9%), crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 3.81-3.74 (m, 4H), 3.36-3.29 (m, 4H),3.25-3.15 (m, 4H), 2.67-2.61 (m, 2H), 2.38-2.31 (m, 2H), 1.81-1.67 (m,4H), 1.63-1.47 (m, 6H).

Example 102-[4-(6-Hydroxypyridin-2-yl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A16”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 6-piperazin-1-ylpyridin-2-ol (91.3 mg; 0.51 mmol) are reactedin isoamyl alcohol (1 ml) in accordance with the procedure for Example 9and worked up. The crude product obtained after conventional work-up ispurified by column chromatography, triturated with diethyl ether,filtered off with suction and dried; yield: 17 mg (10%), crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.04 (bs, 1H), 10.38 (bs, 1H),7.43-7.28 (m, 1H), 6.21-6.05 (m, 1H), 5.88 (d, J=7.9 Hz, 1H), 3.67-3.57(m, 4H), 3.50-3.37 (m, 4H), 2.43-2.33 (m, 2H), 2.29-2.17 (m, 2H),1.72-1.56 (m, 4H).

Example 112-(4-Benzoylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A17”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol), phenylpiperazin-1-ylmethanone hydrochloride (115.5 mg; 0.51 mmol)and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol(1 ml) in accordance with the procedure for Example 9 (reaction time 6h) and worked up. The crystals obtained after purification by columnchromatography are dissolved in acetonitrile and water and freeze-dried;yield: 47 mg (27%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.12 (bs, 1H), 7.52-7.36 (m, 5H),3.84-3.32 (m, 8H), 2.43-2.31 (m, 2H), 2.31-2.16 (m, 2H), 1.74-1.54 (m,4H).

Example 12N-pyridin-2-yl-2-[4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)piperazin-1-yl]-acetamide(“A18”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol), N-(2-pyridyl)-2-(piperazin-1-yl)acetamide * 3HCl * 2H₂O (279.5mg; 0.76 mmol) and triethylamine (282.5 μl; 2.04 mmol) are reacted inisoamyl alcohol (2 ml) in accordance with the procedure for Example 9(reaction time 8 h) and worked up. The crystals obtained are dissolvedin acetonitrile and water and freeze-dried; yield: 19 mg (10%),crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.06 (bs, 1H), 9.97 (bs, 1H),8.36-8.28 (m, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.85-7.74 (m, 1H), 7.16-7.07(m, 1H), 3.65-3.53 (m, 4H), 3.23 (s, 2H), 2.61-2.54 (m, 4H), 2.40-2.31(m, 2H), 2.27-2.19 (m, 2H), 1.72-1.53 (m, 4H).

Example 132-(4-Acetylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A19”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and N-acetylpiperazine (98 mg; 0.76 mmol) are reacted in isoamylalcohol (1 ml) in accordance with the procedure for Example 1 (reactiontime 8 h) and worked up. The crude product obtained in this way ispurified by column chromatography; yield: 12 mg (8%), crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.11 (bs, 1H), 3.61-3.40 (m, 8H),2.41-2.32 (m, 2H), 2.28-2.20 (m, 2H), 2.02 (s, 3H), 1.70-1.57 (m, 4H).

Example 142-[4-(Morpholine-4-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A20”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and piperazinocarboxylic acid morpholide (152.3 mg; 0.76 mmol) arereacted in isoamyl alcohol (1.5 ml) in accordance with the procedure forExample 1 (reaction time 8 h) and worked up. The crystals obtained aredissolved in acetonitrile and water and freeze-dried; yield: 38 mg(21%), crystals;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.11 (bs, 1H), 3.66-3.45 (m, 8H),3.24-3.07 (m, 8H), 2.42-2.32 (m, 2H), 2.31-2.17 (m, 2H), 1.74-1.54 (m,4H).

Example 152-[4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)piperazin-1-yl]-N-pyridin-3-ylacetamide(“A23”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol), N-(3-pyridyl)-2-(piperazin-1-yl)acetamide * 3HCl (251.9 mg; 0.76mmol) and triethylamine (282.5 μl; 2.04 mmol) are reacted in isoamylalcohol (2 ml) in accordance with the procedure for Example 1 (reactiontime 4 h) and worked up.

Example 162-(4-Trifluoromethylpiperidin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A10”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol), 4-trifluoromethylpiperidine * HCl (97 mg; 0.51 mmol) andtriethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1ml) in accordance with the procedure for Example 1 (reaction time 4 h)and worked up. The crude product obtained in this way is purified bycolumn chromatography; yield: 43 mg (28%), crystals;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.06 (bs, 1H), 4.38 (d, J=12.5 Hz,2H), 2.94-2.73 (m, 2H), 2.67-2.45 (m, 1H), 2.43-2.30 (m, 2H), 2.30-2.17(m, 2H), 1.81 (d, J=12.7 Hz, 2H), 1.74-1.52 (m, 4H), 1.46-1.24 (m, 2H).

Example 172-[4-(4-Methoxyphenyl)-3-oxopiperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“A14”)

2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51mmol) and 1-(4-methoxyphenyl)piperazin-2-one (105 mg; 0.51 mmol) arereacted in isoamyl alcohol (1 ml) in accordance with the procedure forExample 1 (reaction time 4 h) and worked up. The crude product obtainedin this way is purified by column chromatography; yield: 8 mg (4%),crystals; HPLC method P; RT/min 2,87.

Analogously, the following compounds are obtained

HPLC method; compound nr. name and/or structure RT/min “A3”2-[4-(4-methoxy-phenyl)-piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.93 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.10 (s, 1H), 6.99-6.89 (m,2H), 6.87-6.77 (m, 2H), 3.74-3.60 (m, 7H), 3.08-2.94 (m, 4H), 2.43-2.31(m, 2H), 2.29-2.18 (m, 2H), 1.74-1.55 (m, 4H) “A22”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]pyridine-3- carboxamide  

“A24”2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

“A26”2-[4-[2-(2-pyridyl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.46 ¹H NMR (400 MHz, DMSO-d₆ + TFA-d₁) δ [ppm] 9.00-8.92 (m, 1H),8.62-8.54 (m, 1H), 8.12-8.06 (m, 1H), 8.04-7.95 (m, 1H), 4.18-3.99 (s,4H), 3.73-3.65 (m, 2H), 3.64-3.51 (m, 6H), 2.73-2.65 (m, 2H), 2.44-2.34(m, 2H), 1.85-1.67 (m, 4H) “A27”2-[4-(piperidine-2-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

“A28”4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazine-2-carboxamide 

“A30”(2R)-1-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazine-2-carboxamide 

“A32”2-[4-(3-pyridyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.49 ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.17 (s, 1H), 8.33 (d, J =2.9 Hz, 1H), 8.05-7.97 (m, 1H), 7.42-7.32 (m, 1H), 7.26-7.18 (m, 1H),3.76-3.61 (m, 4H), 3.27-3.20 (m, 4H), 2.43-2.34 (m, 2H), 2.31-2.19 (m,2H), 1.73-1.55 (m, 4H) “A33”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]benzonitrile 

P; 3.03 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.13 (s, 1H), 7.76-7.67 (m,1H), 7.65-7.56 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.16-7.06 (m, 1H),3.77-3.66 (m, 4H), 3.23-3.13 (m, 4H), 2.44-2.33 (m, 2H), 2.30-2.19 (m,2H), 1.73-1.56 (m, 4H) “A34”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]benzamide 

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.11 (s, 1H), 8.35 (s, 1H), 7.69 (dd,J = 7.7, 1.7 Hz, 1H), 7.48 (s, 1H), 7.42 (ddd, J = 8.1, 7.3, 1.8 Hz,1H), 7.21-7.16 (m, 1H), 7.13 (td, J = 7.5, 1.1 Hz, 1H), 3.70 (t, J = 4.8Hz, 4H), 2.96 (t, J = 5.0 Hz, 4H), 2.42-2.34 (m, 2H), 2.29-2.21 (m, 2H),1.72-1.57 (m, 4H) “A35”2-(4-hydroxy-4-phenyl-1-piperidyl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

P; 2.83 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.96 (s, 1H), 7.52-7.43 (m,2H), 7.36-7.27 (m, 2H), 7.25-7.14 (m, 1H), 5.07 (s, 1H), 4.29-4.13 (m,2H), 3.30-3.14 (m, 2H), 2.41-2.31 (m, 2H), 2.31-2.17 (m, 2H), 1.93-1.80(m, 2H), 1.73-1.55 (m, 6H) “A36”2-[4-(4-fluoro-2-methoxy-phenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.06 (s, 1H), 6.96-6.83 (m, 2H),6.75-6.63 (m, 1H), 3.82 (s, 3H), 3.66 (t, J = 4.7 Hz, 4H), 2.93 (t, J =4.7 Hz, 4H), 2.43-2.35 (m, 2H), 2.31-2.20 (m, 2H), 1.76-1.57 (m, 4H)“A37”2-[4-(2,4-dimethoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.89 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.14 (s, 1H), 6.83 (d, J =8.6 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.71(s, 3H), 3.69-3.58 (m, 4H), 2.93-2.80 (m, 4H), 2.42-2.32 (m, 2H),2.30-2.19 (m, 2H), 1.71-1.56 (m, 4H) “A38”2-[4-(2-chloro-4-methoxy-phenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

“A39”2-[4-(2-chloro-4-fluoro-phenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.10 (s, 1H), 7.42 (dd, J = 8.6, 2.9Hz, 1H), 7.27-7.11 (m, 2H), 3.69 (t, J = 4.7 Hz, 4H), 2.96 (t, J = 4.9Hz, 4H), 2.43-2.35 (m, 2H), 2.31-2.21 (m, 2H), 1.73-1.58 (m, 4H) “A40”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]acetamide 

“A42”2-[4-(2-isopropoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 3.15 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.07 (s, 1H), 6.97-6.84 (m,4H), 4.60 (hept, J = 6.1 Hz, 1H), 3.71-3.60 (m, 4H), 3.05-2.95 (m, 4H),2.41-2.32 (m, 2H), 2.30-2.19 (m, 2H), 1.72-1.56 (m, 4H), 1.30-1.24 (d, J= 6.0 Hz, 6H) “A43”2-[4-[2-(trifluoromethoxy)phenyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.10 (s, 1H), 7.37-7.26 (m, 2H), 7.18(dd, J = 8.1, 1.6 Hz, 1H), 7.10 (ddd, J = 8.1, 7.3, 1.6 Hz, 1H), 3.66(t, J = 4.9 Hz, 4H), 3.02 (t, J = 4.9 Hz, 4H), 2.42-2.34 (m, 2H),2.29-2.20 (m, 2H), 1.73-1.55 (m, 4H) “A44”2-[4-(6-methoxypyridazin-3-yl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.55 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.12 (s, 1H), 7.43 (d, J =9.6 Hz, 1H), 7.05 (d, J = 9.6 Hz, 1H), 3.90 (s, 3H), 3.66 (t, 4H), 3.49(t, 4H), 2.43-2.34 (m, 2H), 2.29-2.20 (m, 2H), 1.72-1.55 (m, 4H) “A45”4-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]benzonitrile 

“A46”2-[4-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]phenyl]acetonitrile  

P; 2.95 ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.1 (brs, 1H), 7.24-7.16 (m,2H), 7.02-6.95 (m, 2H), 3.88 (s, 2H), 3.67 (t, J = 5.2 Hz, 4H), 3.17 (t,J = 5.2 Hz, 4H), 2.45-2.35 (m, 2H), 2.28-2.20 (m, 2H), 1.72-1.56 (m, 4H)“A47”2-[4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

“A48”2-[4-(4-ethoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

P; 3.02 ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.09 (s, 1H), 6.96-6.87 (m,2H), 6.86-6.76 (m, 2H), 3.94 (q, J = 6.9 Hz, 2H), 3.66 (t, J = 5.0 Hz,4H), 3.02 (t, J = 5.1 Hz, 4H), 2.44-2.34 (m, 2H), 2.19-2.28 (m, 2H),1.73-1.56 (m, 4H), 1.29 (t, J = 7.0 Hz, 3H) “A49”2-[4-(4-isopropoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

“A50”2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 3.29 ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.13 (s, 1H), 7.52 (d, J =8.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 3.68 (t, 4H), 3.34 (t, 4H),2.43-2.35 (m, 2H), 2.29-2.20 (m, 2H), 1.74-1.56 (m, 4H) “A51”2-[4-(6-methoxy-3-pyridyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

N; 1.82 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 7.81 (d, J = 3.0 Hz, 1H), 7.48(dd, J = 9.0, 3.1 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 3.78 (s, 3H), 3.68(t, J = 5.1 Hz, 4H), 3.06 (t, J = 5.1 Hz, 4H), 2.43-2.33 (m, 2H),2.29-2.19 (m, 2H), 1.74-1.56 (m, 4H) “A52”2-[4-(5-methoxy-2-pyridyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

“A21”2-[4-(3-aminopropanoyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

“A25”2-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

P; 2.37 ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.96 (s, 1H), 4.38 (t, 1H),3.56-3.45 (m, 6H), 2.47-2.29 (m, 8H), 2.28-2.17 (m, 2H), 1.71-1.54 (m,4H) “A29”2-[3-(hydroxymethyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

“A31”2-[(2R)-2-(hydroxymethyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

“A41” 2-(3-phenylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one 

“B1”2-(4-tert-butyl-piperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.48 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁) δ [ppm] 4.67 (d, J = 14.6 Hz,2H), 3.71 (d, J = 12.1 Hz, 2H), 3.64-3.46 (m, 2H), 3.31-3.15 (m, 2H),2.79-2.67 (m, 2H), 2.48-2.30 (m, 2H), 1.86-1.67 (m, 4H), 1.41 (s, 9H)“A53”2-[4-hydroxy-4-(4-methoxy-phenyl)-piperidin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 2.82 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.93 (s, 1H), 7.42-7.32 (m,2H), 6.90-6.81 (m, 2H), 4.96 (s, 1H), 4.25-4.10 (m, 2H), 3.72 (s, 3H),3.29-3.13 (m, 2H), 2.41-2.31 (m, 2H), 2.29-2.19 (m, 2H), 1.76-1.87 (m,2H), 1.72-1.54 (m, 6H) “A54”2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 3.09 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.97 (s, 1H), 7.22-7.09 (m,2H), 6.96 (dd, J = 8.2, 1.1 Hz, 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H),4.45-4.34 (m, 2H), 3.79 (s, 3H), 3.18-3.06 (m, 1H), 2.96-2.81 (m, 2H),2.41-2.31 (m, 2H), 2.29-2.17 (m, 2H), 1.79-1.45 (m, 8H) “A55”2-[4-(4-methoxy-phenyl)-piperidin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 3.03 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.98 (s, 1H), 7.18-7.11 (m,2H), 6.88-6.81 (m, 2H), 4.43 (d, J = 11.8, 2H), 3.71 (s, 3H), 2.91-2.81(m, 2H), 2.75-2.64 (m, 1H), 2.41-2.33 (m, 2H), 2.27-2.21 (m, 2H),1.79-1.72 (m, 2H), 1.72-1.57 (m, 4H), 1.57-1.45 (m, 2H) “A56”2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

P; 3.30 ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.10 (s, 1H), 7.66 (m, 2H),7.58 (d, J = 8.0 Hz, 1H), 7.41-7.31 (m, 1H), 3.66 (t, J = 4.6 Hz, 4H),2.88 (t, J = 4.9 Hz, 4H), 2.43-2.33 (m, 2H), 2.20-2.30 (m, 2H),1.73-1.57 (m, 4H) “A57”2-[4-[2-(1-hydroxy-1-methyl-ethyl)phenyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one  

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.13 (s, 1H), 7.48 (dd, J = 7.8, 1.7Hz, 1H), 7.43 (dd, J = 7.9, 1.4 Hz, 1H), 7.24 (td, J = 7.5, 1.7 Hz, 1H),7.18 (td, J = 7.5, 1.4 Hz, 1H), 7.10 (s, 1H), 4.55-4.25 (m, 2H),3.05-2.75 (m, 6H), 2.44-2.32 (m, 2H), 2.30-2.21 (m, 2H), 1.73-1.57 (m,4H), 1.51 (s, 6H).Pharmacological Data

TABLE 2 Inhibition of tankyrases of some representative compounds of theformula I EC₅₀ IC₅₀ IC₅₀ Compound tankyrase 1/2 tankyrase 1 tankyrase 2No. (cell assay) (enzyme assay) (enzyme assay) “A3” B B B “A5” C B B“A6” B B B “A7” B A B “A8” C B B “A9” B A B “A10” C B B “A11” B B B“A12” B A B “A13” C B B “A14” C C C “A15” C C C “A16” C C C “A17” C C“A18” C B B “A19” C C C “A20” C C C “A25” C C “A26” B B “A32” B B “A33”B A B “A34” A B “A35” B B B “A36” B A B “A37” B B B “A39” B B B “A42” BB “A43” B C “A46” B B “A48” B B “A50” B B “A51” B B B “A53” B B B “A54”B A B “A55” C A B “A56” B A B IC₅₀: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

The compounds shown in Table 1 are particularly preferred compoundsaccording to the invention.

TABLE 3 Inhibition of tankyrases and PARP1 of some representativecompounds of the formula I IC₅₀ IC₅₀ Compound tankyrase 1 tankyrase 2IC₅₀ No. (ELISA assay) (ELISA assay) PARP1 “A3” A A A “A5” A A “A6” A AB “A7” A A B “A8” A A “A9” A A B “A10” A A “A11” A A “A12” A A B “A33” AA B “A34” A A A “A36” A A B “A37” A A “A39” A A “A48” A A “A50” “A51” BB “A53” “A54” A A “A55” A A “A56” A A IC₅₀: <0.3 μM = A 0.3-3 μM = B3-50 μM = C

The following examples relate to medicaments:

Example A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of the formula I in 601 ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. A compound selected from the followingcompounds: No. Name and/or structure “A5”2-[4-(3-fluorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A6”2-[4-(4-fluorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A8”2-[4-(4-chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A9”2-[4-(2-chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A10”2-(4-trifluoromethylpiperidin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A11”2-[4-(3-chlorophenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A13”2-(4-tert-butylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin- 4-one“A14” 2-[4-(4-methoxyphenyl)-3-oxopiperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A15”2-[4-(piperidine-1-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A16”2-[4-(6-hydroxypyridin-2-yl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A18”N-pyridin-2-yl-2-[4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)piperazin-1-yl]acetamide “A19”2-(4-acetylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4- one “A20”2-[4-(morpholine-4-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A21”2-[4-(3-aminopropanoyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A22”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]pyridine-3-carboxamide “A23”2-[4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)piperazin-1-yl]-N-pyridin-3-ylacetamide “A24”2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A25”2-[4-(2-hydroxyethyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A26”2-[4-[2-(2-pyridyl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A27”2-[4-(piperidine-2-carbonyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A28”4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazine-2- carboxamide“A29” 2-[3-(hydroxymethyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A30”(2R)-1-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazine-2-carboxamide “A31”2-[(2R)-2-(hydroxymethyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A32”2-[4-(3-pyridyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H- quinazolin-4-one“A33” 2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]benzonitrile “A34”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]benzamide “A35”2-(4-hydroxy-4-phenyl-1-piperidyl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A36”2-[4-(4-fluoro-2-methoxy-phenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A37”2-[4-(2,4-dimethoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A38”2-[4-(2-chloro-4-methoxy-phenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A39”2-[4-(2-chloro-4-fluoro-phenyl)piperazin-1-yl]-5,6,7,8-tetra-hydro-3H-quinazolin-4-one “A40”2-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]acetamide “A41”2-(3-phenylpiperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4- one “A42”2-[4-(2-isopropoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A43”2-[4-[2-(trifluoromethoxy)phenyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A44”2-[4-(6-methoxypyridazin-3-yl)piperazin-1-yl]-5,6,7,8-tetra-hydro-3H-quinazolin-4-one “A45”4-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]benzonitrile “A46”2-[4-[4-(4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-2-yl)piperazin-1-yl]phenyl]acetonitrile “A47”2-[4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A48”2-[4-(4-ethoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A49”2-[4-(4-isopropoxyphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A50”2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A51”2-[4-(6-methoxy-3-pyridyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A52”2-[4-(5-methoxy-2-pyridyl)piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A53”2-[4-hydroxy-4-(4-methoxy-phenyl)-piperidin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A54”2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A55”2-[4-(4-methoxy-phenyl)-piperidin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one “A56”2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-yl]-5,6,7,8-tetra-hydro-3H-quinazolin-4-one “A57”2-[4-[2-(1-hydroxy-1-methyl-ethyl)phenyl]piperazin-1-yl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one

or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomerthereof, including mixtures thereof in all ratios.
 2. The compound2-(4-tert-butyl-piperazin-1-yl)-5,6,7,8-tetrahydro-3H-quinazolin-4-one(“B1”), or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios.
 3. Amedicament composition comprising at least one compound according toclaim 1 or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios, and apharmaceutically acceptable carrier, excipient or vehicle.
 4. Amedicament composition comprising at least one compound according toclaim 1 or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios, and atleast one further medicament active ingredient.
 5. A kit comprisingseparate packs of (a) an effective amount of a compound according toclaim 1 or a pharmaceutically acceptable solvate, salt, tautomer orstereoisomer thereof, including mixtures thereof in all ratios, and (b)an effective amount of a further medicament active ingredient.